The present invention relates to a mixing device for mixing solution in a well plate.
Multi-well plates, which are also called microplates, micro-well plates, microtiter plates, or the like, are widely used as an experimental or testing instrument in the field of study in medical science, pharmaceutics, biochemistry, chemistry, and the like. The multi-well plate generally has, for example, 6, 24, 96, 384, or 1536 wells. Each of the wells is capable of containing approximately 1 microliter to several milliliters of reaction solution. A plate reader is used for detecting the solution after reaction. Moreover, an automatic solution addition and suction device for adding solution and washing wells, a conveyance system for conveying a plate itself, and the like are commercially available as general-purpose products from various manufacturers.
A cell-based assay for evaluation of function on a cell-by-cell basis has recently attracted attention. Multi-well plates are often used therefor. For a measurement format used in the cell-based assay, a 96-well plate is predominant, and a 16-well plate and a 384-well plate are also used. Mixing control is important in cell culture and measurement. In the mixing control, it is necessary to mix solution without damaging cells sticking to the bottom or floating cells. Thus, highly accurate mixing is necessary. Since a small amount of reaction solution is contained in a well, if the reaction solution evaporates, it may be difficult to sufficiently mix the reaction solution. In addition, cells contained therein may be damaged. In particular, if volatile reaction solution is used, it is very important to inhibit evaporation of the reaction solution.
It is said that 70% of medicine has a plurality of crystal forms. The solubility and stability are different in each of the crystal forms. Therefore, it is necessary to evaluate as many crystal forms as possible in development processes. In screening such crystal polymorphism, a technology of high-throughput screening in which detailed conditions such as the solution composition, the temperature, and the mixing speed of compound solution are set and crystal forms generated under each of the conditions are evaluated is useful. Also in this case, the multi-well plate is often used. Regarding mixing, horizontal vortex mixing or mixing with a magnetic stirrer is used. In the method using the magnetic stirrer, a setting range of mixing revolutions per minute (rpm) is narrow, and it is not easy to achieve low-speed and high-speed mixing. Further, due to low reliability of motion of the stirrer, if the rotation followability is low, it lowers the mixing efficiency. Further, there is also a problem that the mixing device itself is large in size. Most problematic is that a magnet stirrer disposed on a bottom surface grinds generated crystals during mixing and accurate evaluation results cannot be obtained. Further, in any methods, only one mixing condition can be set in all the wells. Thus, it is desirable to be capable of setting the mixing rpm corresponding to each of the wells in order to consider many detailed mixing conditions. In crystal screening, paddle mixing is often used for scale-up, and hence it is favorable to use paddle mixing also in small-scale experiments.
For synthesis of medicines, high-throughput synthesis techniques represented by combinatorial chemistry is desirable. Synthesis approaches using a microplate have been carried out many times in the past. Typically, horizontal vortex mixing or mixing using a magnetic stirrer is employed. For synthesis of medicines, paddle mixing is often used for scale-up, and hence it is favorable to use paddle mixing also in small-scale experiments.
WO 2016/116972 (hereinafter, referred to as Patent Literature 1) describes a mixing device that mixes solution in a well by using paddle mixing for each of wells of a multi-well plate. In Patent Literature 1, a mixing rod is connected to a motor shaft of a motor and the mixing rod rotates due to activation of the motor for mixing. In the mixing device described in Patent Literature 1, a seal is provided between the mixing rod and a bearing fixed on a motor chassis. Thus, a space communicating with liquid to be mixed is isolated from the bearing fixed on the motor chassis and the liquid to be mixed is inhibited from splashing onto the bearing.
Further, Japanese Patent Application Laid-open No. 2007-74900 (hereinafter, referred to as Patent Literature 2) describes a mixing device using a magnetic coupling mechanism. In Patent Literature 2, in order to mix matter to be mixed in a hermetically sealed container, a driving rotator capable of being rotationally driven by an electric motor is magnetically coupled with a driven rotator on which a mixing blade is mounted, and matter to be mixed is mixed due to activation of the electric motor. In Patent Literature 2, matter that can be mixed only under a hermetically sealed state or matter to be mixed under a high-temperature and high-pressure environment or under vacuum is sealed in the hermetically sealed container. The hermetically sealed container is hollow as a whole and has no openings. The mixing blade, part of a driven shaft on which the mixing blade is mounted, and part of a magnetic rotation transmitter are housed in a hermetically sealed state in the hermetically sealed container. The hermetically sealed container is composed of at least two parts and hermetically sealed with a bolt and a seal member or the like. After mixing, the hermetically sealed container is disassembled within a hermetically sealed box, and the mixed matter is taken out.